Therapeutic strategies aiming to promote immune responses against tumors are of great interest for their potential to destroy metastatic cancer despite its genetic heterogeneity and ability to evade traditional chemotherapy or targeted drugs. Therapeutic vaccines are particularly compelling, because of their low toxicity and broad applicability to diverse human cancers. Recently, the first signs of therapeutic efficacy in cancer vaccines have begun to be reported, and the first cancer vaccine to be approved by the FDA (the cellular vaccine Provenge) was licensed in 2010. Vaccines based on polypeptide antigens, such as long peptides (peptides of 20-40 amino acids that can be processed and presented by diverse human HLAs) are much simpler to manufacture and have also recently begun to show signs of efficacy in patients. However, such vaccines, typically formulated as soluble polypeptides mixed with various adjuvant compounds, leave much room for improvement in terms of their potency in promoting T-cell responses. In an effort to enhance polypeptide vaccines, we sought a readily translatable strategy to enhance vaccine targeting to lymph nodes, where immune responses are initiated. Taking cues from another area of clinical cancer management, we noted that identification of sentinel lymph nodes (LNs) draining sites of primary tumor resection is often performed by the injection of dyes that avidly bind to the ubiquitous serum protein albumin. Albumin-binding dyes are efficiently carried through lymphatics and accumulate in the lymph node, allowing visual identification of the draining nodes following surgery. Mimicking this process, we designed molecular vaccines composed of peptide antigens or immunostimulatory oligonucleotides (single-stranded CpG oligos) conjugated to lipophilic tails with an intervening polymer or oligonucleotide spacer. Strikingly, when these lipid-polar block vaccine amphiphiles were synthesized with (i) lipophilic tails exhibiting high affinity for albumin and (ii) long polar spacers/cargos, they exhibited dramaticall enhanced (>10-fold) accumulation in LNs following parenteral injection relative to soluble peptide/CpG. This enhanced LN targeting of both antigens and molecular adjuvants elicited dramatically enhanced CD8+ T-cell responses, comparable to viral vectors. Based on this promising preliminary data, we propose to establish the mechanisms by which these albumin-hitchhiking amphiphile vaccines function and to test the extensibility of this approach to other adjuvant and immunomodulatory factors. In addition, we have discovered that amph-vaccines efficiently transit across the airway mucosa, and we will test the capacity of pulmonary amphiphiles to serve as simultaneous vaccines priming new T-cell responses in draining LNs and direct modulators of the lung tumor microenvironment in models of lung metastasis and primary GEM lung adenocarcinomas.